Viral Hepatitis

Yonghong Zhang M.D. D.Phil. Beijing Youan Hospital Capital Medical University

Beijing Youan Hospital, Capital Medical University

What is hepatitis?

What can we learn from hepatitis?

Clinical manifestation Diagnosis Principle of treatment

How can we study hepatitis?

Epidemiology Etiology Pathogenesis Clinical role of laboratory detection on viral antigen and antibody
Beijing Youan Hospital, Capital Medical University

What is hepatitis?

What can we learn from hepatitis?

Clinical manifestation Diagnosis Principle of treatment

How can we study hepatitis?

Epidemiology Etiology Pathogenesis Clinical role of laboratory detection on viral antigen and antibody
Beijing Youan Hospital, Capital Medical University

What is Hepatitis?
Hepatitis implies injure to the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from ancient Greek hepar or hepato, meaning liver, and suffix-itis, meaning inflammation.

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Inflammation of liver
Normal liver

virus
Alcohol

hepatotropic virusAE) non-hepatotropic virus

Fatty Liver very common

Inflammatory liver

Drug Autoimmune Disease Inherited metabolism Chemical poisoning Others such as

RedSwellingHotPain

hepatic ischemia

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Viral Hepatitis
Viral

hepatitis is a generalized disease caused by a

group of viruses known as the hepatitis viruses

Most

cases with liver damage worldwide

Yellow Fever VirusYFV

Epstein-Barr VirusEBV
CytomegalovirusCMV Herpes Simplex VirusHSV Rubella Virus (RV)

Not Hepatitis viruses

Secondary liver damage

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Viral Hepatitis
type A virus HAV RNA
type B virus HBV DNA type C virus HCV RNA type D virus (HDV RNA type E virus HEV RNA Hepatitis G virus (HGV/GBV-C) transfusion-transmitted virus (TTV)

Beijing Youan Hospital, Capital Medical University

What is hepatitis?

What can we learn from hepatitis?

Clinical manifestation Diagnosis Principle of treatment

How can we study hepatitis?

Epidemiology Etiology Pathogenesis Clinical role of laboratory detection on viral antigen and antibody
Beijing Youan Hospital, Capital Medical University

Hepatitis A
Hepatitis A is an acute liver disease caused by the hepatitis A virus (HAV), lasting from a few weeks to several months. It does not lead to chronic infection.

Greenland

Mongolia China India

Africa South America
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Hepatitis A--Etiology

HAV is a RNA virus, a member of the Picornaviridae family Naked RNA virus 27-32 nm in diameter One stable serotype only Inactivated by ultraviolet rays, formalin, boiling water

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Hepatitis A--Etiology
One stable serotype only one antibody system

Anti-HAV-IgMbiomarker of acute infection Anti-HAV-IgGbiomarker of protective antibody

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Hepatitis A--Epidemiology
Source of infection
acute stage of patients and covert infectioners

infectivity
2 weeks before clinical illness to 1 week after the period of apparent manifestation Most strong in stage of preicteric No infectivity after 4 weeks of illness

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Hepatitis A--Epidemiology

Route of transmission

Enterically (fecal-oral route) Sporadic occurrence

Close personal contact, common in clinic (e.g., household contact, child day care centers)

Epidemic

Contaminated food, water

raw shellfish in 1988,Shanghai,

310,000/HAV infection-47 death

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Hepatitis A--Epidemiology

Susceptibility of the crowd

Most in children and adolescent Covert infection is common Long-term immunity after infection Anti-HAVIgG+in 90% of adult above 40 years

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Hepatitis E
Hepatitis E is very similar with hepatitis A infection, an acute liver disease caused by the hepatitis E virus (HEV). It does not lead to chronic infection.

Greenland

Africa South America

China India

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Hepatitis E--Etiology
HEV was found in 1983 from feces of patients Nonenveloped spherical RNA virus 32-34 nm in diameter 3 open reading frames (ORFs) No vaccine Inactivated by chloroform and boiling water

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Hepatitis E--Etiology

Anti-HEV-IgMbiomarker of acute infection

Anti-HEV-IgGlast for 1 year, to be used in epidemiology survey, while not protective antibody
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Hepatitis E--Epidemiology
Similar with Hepatitis A in source of infection and route of transmission Unique features
Epidemic associated with contaminated water Covert infection is common Fatality rate was quite high in patients with chronic HBV infection or pregnant Seasonspring and winter

Anti-HEV IgG last in short period, seldom last for 1 year

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Hepatitis B
Hepatitis B is a liver disease caused by the hepatitis B virus (HBV). It ranges in severity from a mild illness, lasting a few weeks (acute), to a serious long-term (chronic) illness that can lead to liver disease or liver cancer.
Greenland

Mongolia China India

Africa South America
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Hepatitis B--Etiology

HBV is a hepatotropic DNA virus Dane particle was discovered in 1970

Large spherical Dane particles
42 nm in diameter Consist of outer coat and core

Small spherical particles

Approximately 22 nm

Only with HBsAg Without infectivity

Tubules
22nm in diameter 100-1000nm length

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 Dane particle: double walled spherical structure 42 nm

diameter with HBV DNA

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Hepatitis B--Etiology

HBV genome Partially double-stranded circular DNA , 3.2kb, plus and minus strands Minus strand: 4 ORF (open reading frame)
S regionHBsAg C regionHBcAg HBeAg P regionDNApol.

X regionHBxAg

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Hepatitis B--Etiology

HBV structure protein S gene structural protein Small/major protein: HBsAg Middle proteinHBsAg+PreS2 Large protein: HBsAg+PreS2+PreS1

PreS protein Strong immunogenicity Increase immune response to S protein Adhesion between virus and cell

Middle

Large

Small
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Hepatitis B--Etiology
Meaning of HBsAg and Anti-HBs

Special marker of HBV infection Main component of vaccine

Produce protective antibodyanti-HBs

Appearance of anti-HBs indicates HBV

infection progress to convalescent period

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Hepatitis B--Etiology
C gene including C and Pre C gene
Pre C gene
Translate to P25 (pre HBeAg) Hydrolyze to P22 and P15-18

C gene
Translate to P21 (HBcAg) High immunogenicity

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Hepatitis B--Etiology
Mutation of Pre C gene
G1896ATGGTAG termination codon

Synthesis of HBeAg
stopped HBV DNA positive Synthesis of HBcAg High infectivity

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Hepatitis B--Etiology
P gene encode functional proteins, including DNA polymerase, RNAase H
Promote the replication of virus One of the markers indicate the replication of HBV Target point of antiviral drug--nucleoside analogue

X gene HBxAg Activate regulative genes of HBV Play an important role in the hepatocellular carcinogenesis
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Hepatitis B--Etiology
HBV-DNA
The direct marker of replication and contagiousness of HBV
Quantification of HBV DNA represent the replication and transmissibility of virus To evaluate efficacy of antiviral therapy

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Hepatitis B--Etiology
HBV biomarkers and their clinical significance

HBsAg Anti-HBs HBeAg Anti-HBe

HBcAg Anti-HBc

Antigen and antibody system

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Hepatitis B--Epidemiology
Source of infection
Acute and chronic HBV patients, HBV carriers

Infectivity
Acute HBV patients
Late incubation stage Acute stage

Chronic HBV patients HBV carriers

Related with HBV DNA

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Hepatitis B--Epidemiology

Route of transmission (blood or body fluid containing HBV)

Vertical transmission (mainly in China)

Perinatal transmission Breast feeding

Horizontal transmission

Parenteral/percutaneous transmission

Sexual transmission and other routes

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Hepatitis B--Epidemiology

Susceptible population

People without anti-HBV Infants are at the most risk of infection Physician, dentist, nurse Drug abuse

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Hepatitis B--Epidemiology
Prevalence of HBV infection varies geographically
High(>8%)Southeast Asia, Africa, China Intermediate(2-7%)eastern Europe, Japan, Russia

Low(<2%)North America, western Europe, Australia

Male patients are more than female 1.4:1 No seasonal difference Sporadic occurrence Family gathering

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Hepatitis D--Etiology

HDV is the smallest known hepatitis RNA virus HDV is replication defective in that it is incapable of making its own envelop protein

HDV infection and replication can occur only in a host with HBV infection

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Hepatitis D--Etiology
HDAg and anti-HDV
HDAg is direct biomarker of HDV infection

Anti-HDV-IgMearly infection of HDV Anti-HDV-IgGprevious infection of HDV

HDV-RNA-PCR can detect HDV infection

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Hepatitis D--Epidemiology
Source of infection
Acute and chronic HDV patients, HDV carriers

Route of transmission (blood or body fluid containing HDV)

Similar with HBV infection

Susceptible population

Mixed infection:

HBV and HDV infected at same time

Super-infection: HDV infected patients with chronic HBV infection

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Hepatitis C
Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to cirrhosis an liver cancer.
Greenland

Mongolia China India

Africa South America
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Hepatitis C--Etiology

HCV was found in 1989 and it is a singlestranded RNA virus, a member of the flaviviridae family 30-60 nm in diameter

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Hepatitis C--Etiology
Developed countries

America and western Europe

Southern Africa India western Africa

Asia

IVDU

3
Simmonds P, Journal of Hepatology, 1999

6
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Hepatitis C--Epidemiology
Source of infection
Acute and chronic HCV patients, asymptomatic HCV carriers

Route of transmission

Same as HBV infection Transfusion was the most common route

Susceptible population

People are all susceptible population Anti-HCV is not protective and could not prevent HCV infection.
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Comparison amongst virus

HAV

HBV

HCV

HDV

HEV

gene
route chronic detection

RNA
Enteric no anti-HAV IgM anti-HAV IgG

DNA

RNA
blood/body fluid

RNA

RNA
Enteric

yes HBV M

yes anti-HCV

yes HDAg

no anti-HEV IgM

anti-HDV IgM anti-HDV IgG

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